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#1
10-04-2006, 05:16
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Ibogaine-Replacements: Cure for U.S. Opiate Addicts...
This thread is for posting information relevant to several key factors:
1. Curing/Treating Opiate Addiction and/or Withdrawal Symptoms. 2. The Activities and Proposed Mechanisms of Ibogaine Therapy. 3. Possible Therapies that could possibly Mimick the Effects of Ibogaine so that US citizens can benefit from Ibogaine's Success with Opiate-Addicted Persons. Please note that most of these issues have been addressed in previous discussions. However, I would like to discuss specifically how to alleviate WD symptoms and/or reduce opiate cravings based upon both established "kicking" aids as well as by attempts to recreate the pharmacodynamics of Ibogaine as a treatment for habitual, chronic opiate administration. I believe that it might be possible to effectively recreate the ibogaine experience without illegally importing the Iboga plant into the USA. This thread will serve as a spring-board for creative ideas, for research reports dealing with the proposed and proven neurophysiological effects of ibogaine, and as a place to give testimonial evidence as to the effectiveness of various trials. First, I would like to propose a few possibilities for Ibogaine-substitution, or said in another way, "How to relieve opiate withdrawal symptoms in a manner similar to Ibogaine treatment using techniques and compounds that are available to persons without access to Ibogaine." DXM: THE IDEA THAT STARTED THIS THREAD... -according to recent laboratory data, one of the neurochemical effects of Ibogaine is inhibition of the NMDA ion channel. There's another drug which operates in this manner... that drug is called dextromethorphan hydrobromide or DXM for short. For those who are unfamiliar, this agent is an over-the-counter cough remedy that has become notoriously popular for its ability to induce dissociative states--and I would be surprised if there's anyone reading this post who isn't well-familiarized with the effects of recreational-dosed DXM. -my experience w/DXM: I personally experienced this drug many years ago while in college. This was during the time when very few people knew of the hallucinogenic/euphoriant/dissociative properties of DXM... My decision to try the drug despite little user-data was obviously stupid, and I would certainly not advocate anyone to copy my stupidity and try a drug on which very little research had been done... However, I tried the drug anyway, and I experienced its effects at various dosage levels without any preconcieved notions about what the experience would be like. In fact, all I really expected was a "drunk" feeling. Because of this "empty slate" approach to the drug, I was able to truly analyze several of the subjective effects that my friends and I experienced while under the influence of DXM. Relativity of Time. For one, I noticed that on DXM, time seemed to stand still. Everyone is familiar with the relative nature of time. If you're not sure what this is, then try standing on your head for 15 minutes while watching the second-hand of a clock slooowly tick away around the clock for 15 full cycles. Then remember the last time you had sex or rode a roller-coaster or stood in line at the DMV for 15 minutes. These examples demonstrate that we--as humans--experience time in a subjectively relative manner. Well, DXM made time stand still. One night seemed like 2 weeks. Occasionally, I would carry on conversations for seemingly hours-on-end, only to find that 7 minutes had passed. Repeated Imagery and Themes. While under the influence of a DXM 'trip,' I noticed that the experience was extremly "thematic." By this, I mean that there was always one or more repeating ideas, visions, thoughts, analyses, obsessions, or self-focuses that would essential repeat itself over and over again throughout the experience. Remember, when your subjective experience of time crams 2-3 months into a short 8-10 hours, repetition can have a profound effect in maximizing the learning and personal growth potential of that 10 hours. Ability to Induce Personal Changes. Believe it or not, I actually discovered for myself an amazing power of DXM to institute changes in my own behavioral patterns, habits, addictions, and motivations. I have since heard of this being a common experience, but for me it was nothing short of an answered prayer from God. Examples of changes that I was able to institute, fortify, and maintain after a half-hearted intention to change myself before & during a DXM experience: I stopped skipping classes almost 3 months into a semester of non-attendance--followed by an overall semester GPA of 4.0; I quit smoking (not permanent, but did last approximately 4 months--pretty good considering I was still a reckless teenager); I stopped smoking pot due to its effect on my activities of daily living (this worked forever--even after 10+ years, I have been largely turned-off by MJ. Prior to the DXM session, I had been smoking 3-5 times/day and refusing to leave my house unless absolutely necessary for about 18 months. How did these changes take place??? I have absolutely no idea. I did not enter the experience with any expectations about changing my life. The problems were already existent in the back of my mind... It seemed like the DXM caused me to reflect deeply on these problems that I had successfully ignored for quite some time. Since this is a subjective experience, I have no idea whether the changes were due to physical changes in my brain chemistry or if they were due to merely psychological effects (from introspection, focus, dwelling on problems followed by dwelling on solutions and personal change?). In either case, the reality is that something very real happened for me and I cannot speak for anyone else, nor can I claim to have tested these effects on animals, brain tissues, or any other people. Repulsion to Cigarettes. Smoking cigarettes while doing drugs go together like a cheerleader and a football game for me. If I'm drinking or if I was under the influence of anything else (as a kid), then I was certainly smoking cigarettes at the same time. However, I noticed with my first DXM trip that I had forgotten all about cigarettes--almost like I had forgotten that I was ever even a smoker, until 4-5 hours INTO the experience! Finally, I remembered that I was a smoker, and lit up... GROSS!! I hated cigarettes on DXM. They tasted awful, and I felt like an alien holding them, lighting them, and puffing on them... I'm going out on a limb here to say that this effect is almost assuredly due to the biochemical effects of the DXM. Anyone who has experienced DXM with cigarettes and wellbutrin/Zyban knows what I'm talking about. The effect on cigarette pleasure is almost identical. Exposure of Repressed Memories. This one is a VAST area of potential. I will not get into my own experiences, but suffice it to say that old, previously-forgotten memories can and will surface while under the influence of DXM. According to the reports on Ibogaine, these surfaced memories comprise a very large portion of the subjective psychological self-healing process. Remember: For a heroin addict, the problem is usually not the heroin. Heroin is a shitty solution to the problem. The problem is a poor coping-strategy for life's various curve-balls. It serves as a numbing agent to help you forget about your problems. Apparently Ibogaine (like DXM for me) sets the stage for confrontation of your actual problems. This includes surfacing of old memories, dealing with your own emotional response to forgotten problems, and helping institute a pattern of self-acceptance and self-healing rather than placing a band-aid over the problem, covering it up with mind-numbing drug addictions. Difficulty accessing cortical pathways... I've read posts from other websites where this concept is referred to as "Reptilian brain." A very interesting, and descriptive term that embodies the experience as many higher-functions of the brain are essentially impossible to execute! Another reason why I find this term so intriguing is because of the physical location of the pleasure/reward center of the brain... First, let me explain some taxonomy to those who weren't biology majors in college. The theory of evolution--and the driving force behind taxonomic classification of various animals, plants, fungi, and bacteria is that all species originated from essentially the simplest of organisms... not only that every species started out as a single cell, but that there are common ancestors to essentially every organism we know of in each kingdom--even across kingdoms--but this would have been WAY LONG AGO!  OK, so my point is this: when various animals are studied and dissected, there are big differences in their neurological anatomies--just as there are also obvious differences in their behaviors, moods, and 'personalities.' Reptiles live with only a brain-stem. Anyone who has ever owned a pet snake or a fish knows what I'm talking about. It's food. Sex. Survival. Territory. Food. Sex. Survival. Food. etc... there is no cortex surrounding the brainstem to give way to what we know as "consciousness" or moods or learning--at least not in the sense that we usually define these terms. OK... are you still with me? Well, the pleasure-center is located RIGHT THERE at the top-end of the brainstem/midbrain. This is what tells every reptile, "I'm HUNGRY" or "LET'S HAVE SEX." It is very disturbing to realize that these urges are so centralized and probably explains why so many addicts--whether it's drugs or food--are unable to control their behaviors despite the fact that they spend much of their time thinking about how desperately the WANT to QUIT!!! So, my thoughts are that with all this activity around the reptile-brain, maybe the Ibogaine (and DXM) can expend itself re-wiring the BASIC URGES!! Another good benefit from this focus is that there's a good possibility that the drugs will spare the cortex or 'thinking' part of our brains and their effects on memories, problem-solving, and overall consciousness will be minimal. Now, after having written ALL this, I did a quick search for DXM and I was very disappointed to find that it wasn't ME who discovered all this potential for DXM... the DXM users-guide which is disseminated all over the internet gives credence to DXM's capacity to induce changes and its ability to assist with addiction interuption. In fact, I am SO late in realizing the possibilities of DXM in addiction that I feel like the world's biggest idiot for investing so much time and thought into developing or finding an Ibogaine-replacement. 
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#2
10-04-2006, 23:52
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R_SMOKER'S COMPILATION OF SCIENTIFIC INFORMATION REGARDING IBOGAINE AND OTHERS. NOR-IBOGAINE.18-METHOXY CORONARIDINE (synthetic ibogaine analogue) DEXTROMETHORPHAN. DXO SIMILARITIES OF IBOGAINE AND DXM: 1. Metabolism of Both Drugs By Same Enzyme. Debrisoquine 4-Hydroxylase, aka CYTOCHROME P450-2D6 METABOLISM.Both Ibogaine and DXM are metabolized by the same liver enzyme--P4502D6 Cytochrome Oxidase. 5–10 % of Caucasians lack the gene to produce this enzyme, and are more prone to adverse reactions from drugs metabolised by it; in the remaining individuals, its activity can vary significantly due to minor genetic variance (Gonzalez and Meyer, 1991). In addition, this cytochrome is involved in the metabolism of a number of pharmacological compounds, including neuroleptics, beta-blockers, tricyclic antidepressants, and opioids, raising possible issues of adverse interactions with ibogaine (Eichelbaum and Gross, 1990; Fromm, Kroemer, and Eichelbaum, 1997). Furthermore, individuals lacking this gene are less likely to benefit from the therapeutic effects of drugs metabolised by P4502d6(15-18). (Obach, Pablo, and Mash, 1998). The O-demethylation of ibogaine in the liver is catalysed by the P4502d6 cytochrome, which has important clinical implications (Obach, Pablo, and Mash, 1998). Dextromethorphan is commonly used to determine cytochrome P450-2D6 activity (10-11). P450-2D6 converts DXM into dextrorphan. By looking at the metabolites of DXM, a physician can determine P450-2D6 efficiency, and adjust drug dosage to match. 2. BOTH DRUGS ARE NMDA-RECEPTOR ANTAGONISTS, WITH SIMILARITIES OF MULTIPLE NEURAL NETWORK EFFECTS, MULTIPLE SITES OF ACTIVITY: IBOGAINE: Like many tryptamines (e.g. serotonin, melatonin, d-lysergic acid diethylamide or LSD, psilocybin, N,N-dimethyltryptamine or DMT), the pharmacodynamics of ibogaine are particularly complex, involving multiple sites of action. Ibogaine affects, both directly and indirectly, dopaminergic, glutamatergic, serotonergic, opioid, nicotinic, sigma, gamma-aminobutrylic acidergic (GABA), nicotinic, cholingeric, and muscarinic pathways, as well as calcium regulation and voltage-dependent sodium channels (Popik and Glick, 1996; Glick and Maisonneuve, 1998; Alper et al, 1999; Popik and Skolnik, 1999). It is therefore thought that ibogaine’s effects are a product of a combination of its interactions with these systems. However, there have been a number of discrepancies reported with regard to the specific manners in which ibogaine exerts its pharmacological actions (Popik and Skolnick, 1999). Additionally, noribogaine affects many of the same neural components as ibogaine, which further complicates the study of its pharmacological profile (Mash et al, 2000). DXM: unlike most drugs which target very specific, limited clusters of neurons, DXM tends to affect entire neural nets (via the NMDA receptor). A general "shutdown" or interference with some of these neural nets may produce many of the experiences associated with near-death, and could possibly be mimicked by DXM. Some (very simple) models have demonstrated "spontaneous memory recall" effects when the network is severely disrupted or disconnected & DXM may mimic this. The only problem here is that the NMDA receptor, although extensive, is involved in learning more than "ordinary" neural network signals. The other neural network model: It is possible that, in addition to encoding short-term memory, NMDA receptors are involved in "synchronizing" or "interfacing" the conscious mind to the rest of the brain and body. After all, we experience things in terms of our previous experiences, so raw sensory data must be translated into the "language" of memory before it can be consciously experienced. When enough NMDA receptors are blocked, the mind and body/brain lose the ability to communicate. Each is still capable of "doing its thing", however; in particular this might explain why it is possible to undertake fairly complex tasks under partial or full dissociative anesthesia, but attempting to consciously control these tasks fails. 3. DOPAMINERGIC ACTIVITY: DXM: Many effects are due to indirect activity. dopaminergic activity; DXM has a fairly strong ability to increase dopamine activity (both from activating sigma receptors, and from preventing dopamine reuptake at PCP2 sites) (72,76). IBOGAINE: A great deal of attention has been paid to ibogaine’s effects on the dopaminergic system, as dopamine is theorized to play a primary role in the sensitization, reinforcing, and motivational properties of drugs of abuse (Fibiger and Phillips, 1986; Berrige and Robinson, 1998). Robinson and Berrige (1993) proposed that the incentive salience of drug-taking behaviors is related to neurotransmission in mesotelencephalic dopamine pathways, in which the repeated administration of addictive drugs sensitizes the incentive salience of drug related cues. Compared to drug-naïve individuals, drug addicts have increased sensitivity to both the positive and negative reinforcing effects of drugs of abuse (Grant et al 1996; Ligouri, Hughes, Goldberg, and Callas, 1997; Ellinwood 1968; Angrist, 1983) . These reinforcements are apparently mediated through enhanced brain activity in brain regions innervated by the mesolimbic dopamine system, including the frontal cortex and the amygdala (Alper et al, 1999; Childress et al, 1999). According to this theory, if activity in sensitized dopamine pathways is decreased, it should alleviate addictive drug craving (Blackburn and Szumlinski, 1997). Though ibogaine does not appear to affect binding at dopamine receptors or transporters (Broderick, Phelan, and Berger, 1992), it has been found to reduce extracellular levels of dopamine in the nucleus accumbens (Glick and Maisonneuve, 1998; Glick et al, 1999). Ibogaine effects on dopamine metabolites appear to be inconsistent. When measurements are taken shortly after administration (within 2 hours), or when high concentrations are used (greater than 100 μM), increases in dihydroxyphenyl-acetic acid (DOPAC) and homovanilic acid (HVA) are seen (Maisonneuve, Keller, and Glick, 1991; Maisonneuve, Rossman, Keller and Glick, 1992; Sershen, Hashim, Harsing, and Lajtha, 1992). However, when lower concentrations are used (e.g. 10 μM) or measurements are taken after a longer period of time (up to a week), dopamine brain concentrations remain unchanged, and metabolite concentrations decrease (Maisonneuve, Keller, and Glick, 1991; Shershen, Hashim, Harsing, and Lajtha, 1992). Sershen et al (1994) reported that ibogaine’s effects on dopaminergic function are largely regulated by its interactions with serotonin receptors. This was inferred from their finding that ibogaine inhibited the ability of the 5-HT1b agonist CGS-12066A to increase stimulation induced dopamine release in rat and mouse striatal slices. It has also been demonstrated that ibogaine increased the ability of the 5-HT3 agonist phenylbiguanide to produce stimulation evoked dopamine release in mouse striatal slices (Sershen, Hashim, and Lajtha, 1995). Taken together, these findings support the notion that ibogaine’s effects on serotonin have a role in determining its dopaminergic effects, but the specific nature of this role has yet to be determined. 4. THE GLUTAMANIERGIC PATHWAY: DXM: is an NMDA ANTAGONIST. IBOGAINE: is an NMDA ANTAGONIST. DXO: primarily targets the NMDA receptor while DXM is strongest at the PCP2 and sigma receptors. DXO: more dissociative, intoxicating "stoning" effects. DXM: more stimulation, cognitive alterations, and psychotomimetic (literally, "psychosis-like"). The glutamatergic pathway is also implicated in drug abuse and addiction, specifically N-methyl D-aspartate (NDMA) channel receptors. NMDA antagonists interfere with sensitization, tolerance, and dependence related to stimulant, alcohol, benzodiazepine, barbiturate, and opiate use (Trujillo and Akil, 1991; Wolf and Khansa, 1991; Khanna, Kalant, Shah, and Chau, 1993; File and Fernandez, 1994; Popik and Skolnik, 1996). Furthermore, blockers of NDMA receptors have been show to reduce nalaxone-induced jumping in morphine-dependent mice (Layer et al, 1996; Popik and Skolnick, 1996). NMDA antagonists act by occupying a binding site within a calcium channel, which is normally gated by glutamate, the brain’s principle excitatory neurotransmitter (Helsley, Rabin, and Winter, 2001). Ibogaine acts as a non-competitive antagonist at NDMA receptor channels (Popik et al, 1995), (Glick and Maisonneuve, 1998; Helsey, Rabin, and Winter, 2001). Popik et al (1994) showed that ibogaine substituted for MK-801 (dizocilipine, a known NMDA antagonist) at a rate of approximately 70% in drug discrimination studies in mice. In addition, ibogaine has been shown to inhibit binding of both MK-801 (an NDMA antagonist) and PCP at NDMA receptors (Layer et al, 1996; Helsley et al, 1998). Ibogaine also blocks NMDA-induced convulsions in mice for up to 72 hours after administration (Leal, de Souza, and Elisabetsky, 2000). 5. SIGMA RECEPTORS (PREVIOUSLY KNOWN AS SIGMA OPIOID RECEPTOR) It has been demonstrated that certain sigma ligands may be effective in the treatment of drug abuse, due to their ability to block the behavioral effects of cocaine and amphetamine in non-human subjects (Helsley et al, 1998). Of all binding sites that have been studied thus far, ibogaine shows the greatest affinity for σ2 receptors, with reported K1 values ranging from 90 – 201 nM (Bowen et al, 1995; Mach, Smith, and Childers, 1995). Because of its high affinity for σ2 receptors, ibogaine has been proposed to act as a σ2 agonist (Bowen, Vilner, Bandarage, and Keuhne, 1996). Studies have also shown that ibogaine also binds to σ1 receptors with an affinity of less than 10 μM (Mach, Smith, and Childers, 1995). In support of this finding, ibogaine was shown to inhibit [3H]pentazocine (a σ1 receptor ligand) binding to high and low affinity sites in the mouse cerebellum (Popik and Skolnick, 1999). Bowen et al (1995) hypothesized that ibogaine’s interaction with sigma receptors, particularly σ2 receptors, may be responsible for its effects on the regulation of calcium release from intracellular stores. They found that ibogaine produced a concentration dependent increase of 13 – 45 % in intracellular calcium levels. Additionally, ibogaine was shown to non-competitively antagonize calcium-induced contraction of the aorta and mesenteric artery in the rat (Hajo-Tello et al, 1985). The practical implications, however, of ibogaine’s effects on calcium regulation are not yet clear. 6. OPIOID SYSTEM: Of particular interest with regards to its putative role in interrupting opiate dependence are ibogaine’s effects on the opioid system. Ibogaine is not a conventional opioid agonist or antagonist (Alper et al, 1999). Bhargava et al (1997) found that ibogaine binds to μ-, δ-, and κ-opioid receptors low affinity, 11.0, > 100, and 3.77 μM, respectively. However, noribogaine had considerably higher affinities for these receptors; 2.66 μM for μ-, 24.72 μM for δ-, and 0.96 μM for κ-opioid receptors. These findings have been supported by results showing even higher affinities for noribogaine binding, with affinities of up to 160 nM at the μ-opioid receptor (Pablo and Mash, 1998). It is therefore hypothesized that noribogaine may play a significant role in ibogaine’s effects on opiate dependency (Bhargava, Cao, Zhao, 1997; Mash et al, 2000). INDIRECT EFFECTS ON OPIOID SYSTEM: Ibogaine inhibits the binding of [3h]U-69593 to κ-opioid receptors, with a Ki value of 2 – 4 μM (Repke, Artis, Nelson, and Wong, 1994). However this inhibition is reversible, and therefore is not likely to contribute to ibogaine’s long-term effects (Popick and Skolnick, 1999). Additionally, it has been shown, through a two-site model, that ibogaine inhibits naloxone binding at μ-opioid receptors in the forebrain of mice with a Ki value of 130 nM (Codd, 1995). This suggests that ibogaine may act as μ-opioid agonist of a novel type (Bhargava, Cao, and Zhao, 1997). 7. MESOLIMBIC CATECHOLAMINE SYSTEM: DXM: is an antagonist at the α3β4 nicotinic receptor. IBOGAINE is also an antagonist at the α3β4 nicotinic receptor. Ibogaine, at concentrations < 10 μM, has been shown to selectively inhibit nicotinic receptor mediated catecholamine release in the mesolimbic system (Mah et al, 1998). This inhibition was reversible at low doses (10 μM), but persisted for at least 19 hours with washout at higher doses. Like NDMA and dopaminergic systems, the mesolimbic catecholamine system is implicated in the addictive process. It is considered to be a part of the reward pathway that mediates positive reinforcement in drug addiction (Di Chiara and Imperato, 1988). A recent study by Glick, Maisonneuve, Kitchen, and Fleck (2002) asserts that, although ibogaine and noribogaine exhibit low to moderate binding affinities at many sites, the most critical site of action for the modulation of drug self-administration may be the α3β4 nicotinic receptor. They found that both ibogaine and its synthetic analog 18-methoxycoronaridine exhibit a more potent antagonism at this site than at α4β2 nicotinic receptors, or at NMDA or 5-HT3 receptors. Additionally, co-administration of either ibogaine or 18-methoxycoronaridine at sub-therapeutic doses with another α3β4 antagonist (either mecamyline or dextromethorphan) produced a significant therapeutic response. Because α3β4 receptors are mainly located in the medial habenula and the interpeduncular nucleus, and exist in the dopaminergic nuclei of the ventral tegmental area in only low densities, these researchers suggest that the dopaminergic mesolimbic pathway may not be directly involved in mediating ibogaine’s anti-addictive effects. It is hoped that further study will reveal these mechanisms in more detail. 8. SEROTONIN SYSTEM: DXM: indirectly increases 5HT activity, especially at the 5HT1A receptor. This could explain some of its mood-altering properties. IBOGAINE: increases 5-HT concentrations in both the nucleus accumbens and striatum of the rat (Broderick, Phelan, Eng, and Wechsler, 1994; Ali et al, 1996). However, Benwell et al (1996) found that ibogaine reduces serotonin levels in the medial prefrontal cortex. Furthermore, studies of ibogaine’s specific actions at serotonin receptors have been inconclusive. Deecher et al (1992) found that ibogaine did not displace ligands acting at 5-HT1a, 5-HT1b, 5-HT1c, 5-HT1d, 5-HT2, or 5-HT3 receptors, while Repke et al (1994): it DOES inhibit binding of 5-HT1a, 5-HT2a, and 5-HT3 ligands with low affinity (>100, 12.5, and >100 μM). Additionally, Sweetnam et al showed that ibogaine inhibits radioligand binding to both 5-HT2 and 5-HT3 receptors, with considerably higher affinity (approximately 4 μM), while Helsley et al (1998) found that ibogaine bound to 5-HT2 receptors with low affinity in vitro ( > 40 μM), but occupied this receptor in vivo following systemic administration. It is postulated that ibogaine may act as a reversible inhibitor of serotonin transporters, as concluded from the observation that it inhibited transporters in the isolated kidney cells of pigs (Popik and Skolnick, 1999). Sershen et al (1994) found that, at doses of 40-50 mg/kg, ibogaine decreased levels of 5-hydroxyindoleacetic acid [5-HIAA] in the frontal cortex, hippocampus and olfactory tubercle of the mouse. Ibogaine was also found to decrease 5-HIAA levels in the nucleus accumbens and striatum of the rat, but to increase 5-HIAA levels in the medial prefrontal cortex (Benwell, Holtom, Moran, and Balfour, 1996; Ali et al, 1996). The differing effects of ibogaine on serotonergic function in different areas of the brain have yet to be explained. Indeed, this is the case with most psychedelic compounds, making a strong case for the further scientific study of these substances. 9. ON DOSE BOOSTING: IBOGAINE as utilized by Dr. Mash in her St. Kitt clinic and others, is usually dosed in several (2) different ingestions. DXM: Dose boosting reportedly does NOT work. "By the time you take the second dose, the NMDA receptors have already started to compensate, and saturation of P450-2D6 by 3-methoxymorphinan means that most of the DXM you take won't be nearly as effective. Sigma agonist activity will increase, bringing an overall sense of dysphoria and (temporary) disturbances in thought. Sorry, but there doesn't seem to be an easy way around this; even if you used DXO, the brain still responds quickly to NMDA blockade, as users of ketamine or PCP will attest. Just wait a few days to a week and try again. The one exception to this seems to be a first plateau dose, which (with practice) can be maintained for some time, leading to a prolonged stimulant effect. This is probably due to the dopamine reuptake inhibiting effect of DXM (absent with DXO), similar to that of bupropion (Wellbutrin™) or cocaine. Prolonging this will, however, intensify the "crash" and is probably not a good idea. DXM: DXM binds to at least four sites in the brain (58), which can be arbitrarily labeled DM1, DM2, DM3, and DM4; there is probably also a fifth binding site (DM5). Some of these sites are sensitive to pentazocine, a known sigma ligand; some are sensitive to haloperidol, another sigma ligand. On the following table, information from several sources has been gathered and combined. The binding affinity of DXM, DTG, and 3-PPP are listed (58), along with (+)-pentazocine sensitivity (60), and haloperidol displacement ability (58), (binding values in nM unless otherwise specified). "Low" means micromolar binding affinity. o-------------------------------------------------------------------o | DXM Site | DM1 | DM2 | DM3 | DM4 | |-----------------------+----------+----------+----------+----------| | Probable Binding Site | Sigma1 | PCP2 | Sigma2 | NMDA | |================================================= ==================| | DXM | 50-83 | 8-19 | low | low | |-----------------------+----------+----------+----------+----------| | (+)-3-PPP | 24-36 | low | 210-320 | low | |-----------------------+----------+----------+----------+----------| | DTG | 22-24 | ??? | 13-16 | ??? | |-----------------------+----------+----------+----------+----------| | Pentazocine Sensitive | Yes | No | ??? | ??? | |-----------------------+----------+----------+----------+----------| | Haloperidol Displaced | Yes | ??? | Yes | ??? | o-------------------------------------------------------------------o Table 2: DXM Binding Sites The fourth site is probably the NMDA receptor's open channel site, although it might be the ion channel binding site (59). Contribution of the PCP2 Binding Site The PCP2 binding site is probably the dopamine reuptake complex, so blocking it would prevent the uptake of dopamine in much the same way that the antidepressant bupropion (Wellbutrin[tm]) or cocaine does (73). Of course, DXM is considerably weaker than cocaine (and stronger than bupropion, incidentally) at this site. This probably accounts for the euphoric effects of a low recreational dose, and almost certainly explains the stimulant effects of a low dose. Interestingly, the stimulant effect seems qualitatively different from amphetamines to most people (I have no comparison information on cocaine). One user compared DXM and bupropion favorably in stimulant effect. The music euphoria and motion euphoria are probably partly due to PCP2 activity, and partly due to other activity. As NMDA blockade and sigma activity can both lead to dopaminergic activity (see below), reuptake inhibition would potentiate these effects. Interestingly, DXM seems to be much more potent at this site than other sigma/NMDA ligands (such as PCP or ketamine) in comparison to activity at other sites. Also interestingly, at least one tricyclic antidepressant has been found to be active at related receptors (sigma, PCP) (71,74,75); it is possible that the PCP2 site may be a target of some antidepressants. .................................................. ............................ Contribution of the Sigma Binding Sites As the sigma2 site is a fairly recent discovery, it is not known what sigma-related effects and behaviors are attributable to which receptor (sigma1 or sigma2). There is very little data on the subjective effects of sigma ligands, in part because only recently have selective ligands become available, and in part because most researchers aren't very willing to dose themselves to find out. DXM binds to the sigma1 receptor and is generally considered to be an agonist at this receptor. DXM is probably also an agonist (as opposed to an antagonist) at sigma2, though it is much weaker there. The disruption of sensory processing is probably partly due to sigma activation (and partly due to NMDA blockade) (63-65). Sigma receptors may be specifically involved in the auditory effects of DXM (65), and these effects may relate to a disruption of sensory input persistence. The psychotomimetic (literally "psychosis-like") effects of DXM may be a result of sigma activity (sigma receptors may be involved in schizophrenia) (46-49). People who have used both DXM and ketamine have remarked that DXM is much more likely to induce delusional and hyper-abstract thought patterns. Interestingly, sigma receptors seem to temporarily modulate cholinergic receptors (98), so sigma activity may produce temporary effects somewhat like the delusional anticholinergics. The effects on motor skills may be a result specifically of sigma2 receptors (69). Expect to see more data on this subject as sigma2 receptors are investigated more fully. There may also be a contribution from NMDA receptors, of course. .................................................. ............................ Contribution of the NMDA Receptor Most of the effects on the NMDA receptor are due to DXO (dextrorphan), DXM's main metabolite. DXO, and to a lesser extent DXM, block the NMDA receptor once it opens, essentially by "plugging it up". Most of the "stoning" or intoxicating effects of DXM are probably due to NMDA receptor blockade. Alcohol's intoxicating effect seems to be mediated in part by NMDA receptor blockade (its depressant effect is due to GABA activity; DXM has no activity at GABA receptors) (28,61,62). The dissociative anesthesia of high DXM doses is also likely due to NMDA receptor blockade (63). As stated before, sensory processing disruption, especially at higher doses, is probably due in part to NMDA receptors and partly to sigma (63-65). Flanging, in particular visual flanging, probably derives from NMDA blockade. The effects on memory are almost certainly due to NMDA blockade. NMDA receptors are intimately involved in long-term potentiation (64,66-68), a part of (probably short-term) memory. By blocking NMDA receptors, long-term potentiation, and thus short-term memory, is disrupted. DXM's ability to suppress respiration at toxic levels, is most likely due to NMDA receptor blockade or (in my opinion) ion channel blockade. Some of the effects from very high dosage levels may be due to overall disruption of neural networks. There is some preliminary evidence that both the "spontaneous memory" effect and the sensations similar to near-death experiences may occur as general neural networks are disrupted. Most drugs target specific clusters of neurons, whereas NMDA receptors tend to be more evenly distributed within certain areas of the brain, so blockade of NMDA receptors may be responsible for disruption of some of the brain's neural networks. .................................................. ............................ Contributions of Indirect Activity Many of DXM's effects are undoubtedly due to indirect activity. For example, it may indirectly increase 5HT activity, especially at the 5HT1A receptor. This could explain some of its mood-altering properties. Another example is dopaminergic activity; DXM has a fairly strong ability to increase dopamine activity (both from activating sigma receptors, and from preventing dopamine reuptake at PCP2 sites) (72,76). NMDA receptor blockade also has been shown to increase dopaminergic activity, as well as activity of other neurotransmitter systems (101). .................................................. ............................ The activity of NMDA receptors certainly helps to maintain the normal functioning of the hippocampus. As NMDA receptors become increasingly blocked, individual neurons in the associative network of the hippocampus lose part of their positive input. Although they may compensate by reducing negative input (at GABA receptors, perhaps), the plastic or "learnable" component of neural input will diminish in comparison to the ordinary input (via AMPA and kainate glutamate receptors). Thus it may take more cycles to reach a stable output state. In cortex, NMDA receptors could be much less important, and some aspects of "consciousness" may function mostly via "ordinary" glutamate receptors. If this is the case, then cortical networks would still be operating at normal (or near normal) speed, while the hippocampus slowed down. It is also likely that unstable output from the hippocampus is ignored, or at least dealt with differently than stable, final associative output. Finally, note that raw sensory input probably needs some associative processing before it can reach consciousness, since what we perceive is to some extent "written" in the mental language of our past experiences. Thus, as the hippocampal output slows down and becomes increasingly less stable, one becomes conscious of increasingly less frequent sensory input. Eventually, this becomes infrequent enough that flanging occurs. Finally, with sufficient loss of NMDA function, the hippocampus may never reach a stable state, leading only to chaotic output, totally unconnected to sensory input. But more on that later. .................................................. ............................ and in "plateau 3" the NMDA curve is highest. Due to its increasing affinity for PCP2, sigma1, and NMDA receptors respectively (sigma2 is not represented), a low dose will tend to have proportionally more effect on PCP2 receptors, whereas as the dosage increases, these receptors will saturate. Taking more DXM won't change PCP2 levels much, but will still have a fair effect on other receptors. Furthermore, the more subtle effects on the PCP2 receptors may be all but obliterated by the effects on sigma1 and NMDA receptors (the differing vertical maxima of the three curves represent this effect). This is entirely reasonable, since sigma1 and NMDA activity seem to both produce fairly profound behavioral effects, the latter more so than the former. Thus, the first plateau probably corresponds to predominantly PCP2 activity with some sigma activity and a little NMDA blocking effect; the second plateau to sigma and some NMDA effects; and the third to profound NMDA blockade. .................................................. ............................ As enough NMDA receptors are blocked, one neuron may lose enough input from another that the connection is effectively severed. Initially this isn't such a problem, since both neurons and connections are dense enough so that others can take over the job (although the end result will probably be a slower and less accurate network). At some point, enough connectivity is lost that the network no longer functions. Compare this to the dissociation of the fourth plateau. At some level, some part of the brain (possibly the hippocampus) loses enough functionality that it can no longer operate as a cohesive unit. Sensory processing halts, and raw sensory input cannot be converted to an appropriately parsed output. The consciousness is then left without any real sensory input; instead, the chaotic, unstable patterns are provided. Ergo, dissociative anesthesia. DXM itself is a very complex drug; most drugs only bind to one or two receptors (or at least one class of receptors). Its recreational abuse potential, although known for years, has not been well studied, and it can affect different people very differently. The receptors and binding sites it affects - sigma, NMDA, and PCP2 - are all new discoveries. All this adds up to a complicated and poorly understood drug. Furthermore, the brain itself is a complicated system, and we're still mostly ignorant of its function. The basics of neurotransmission seem to be understood, but many questions remain. Nobody knows why there are so many different neurotransmitters, nor why there are so many receptor subtypes. The second messenger systems of most receptors are not well understood either. A lot of what happens inside neurons occurs via changes in genetic expression, and that's yet another topic about which little is known. What are Sigma Receptors? Sigma receptors (sigma is often written in Greek) are probably one of the most elusive entities in neuropharmacology. Our knowledge of sigma receptors pales in comparison to our ignorance; in fact, what we absolutely know (or at least think we absolutely know) can be summed up very briefly in the following paragraph: Scattered throughout the brain and body there are places (sigma binding sites) where a bunch of chemicals (sigma ligands) happen to stick. We don't know if they're on the outside or inside of cells. We don't know if sticking a chemical to them does anything or not, except in the vas deferens. We don't really know what they do, if they do anything. We don't know what they're for, why they're there, or whether the body uses them. They may be neuroreceptors, steroid receptors, intracellular messenger receptors, growth regulators, enzymes, or something else entirely. In other words, prepare to be confused. Don't worry, everyone else is as well. Sigma receptors were originally thought of as opioid receptors, since many morphine derivatives bind there. However, this classification is probably false, and the endogenous opioid peptides show little sigma activity. The usual characteristics of opiates are mediated by the mu, kappa, and delta receptors. There are at least two sigma receptors, and a third one (sigma3, appropriately enough) has been discovered recently (115). Some researchers have speculated that sigma receptors aren't really receptors at all, but just enzyme binding sites (84). On the other hand, sigma ligands affect the guinea pig vas deferens muscles, which probably wouldn't happen unless sigma receptors really were receptors (98). Sigma receptors may be intended for hormones or intracellular messengers rather than neurotransmitters, as they are present on microsomes rather than on the cell surface (130). .................................................. ........................... Sigma 1 Receptors and General Sigma Information Much of what is known about sigma receptors seems to apply more to sigma1 than sigma2. Endogenous Ligands The neurotransmitter for sigma1 receptors has not been found, although there are speculations and evidence (82-86;99-100). The usual term for the (unidentified) sigma1 neurotransmitter is "endopsychosin" (100), formerly known as "angeldustin". Progesterone targets sigma1 receptors in the placenta, and it and other steroid hormones may be natural ligands for sigma1 receptors (98,103,104). If this is true, it is possible that some of the effects of sex hormones on the brain may be mediated by the sigma1 receptor (98). Substance P (a peptide neurotransmitter) was considered but rejected as an endogenous sigma1 ligand (112). Location and Function in the Brain Sigma receptors are densest in the cerebellar cortex, accumbens nucleus, and cortex, and also present at lower density in the limbic areas and extrapyramidal motor system. This is interesting because some of the bizarre effects of DXM on motion may be related to sigma activity in the cerebellar cortex and extrapyramidal motor system. Sigma1 receptors (and possibly sigma2) appear to be functionally coupled to some other receptors, notably nicotinic acetylcholine receptors (98,117) and NMDA receptors (107-110). The nicotinic receptor coupling may be direct, with sigma activation causing a change in the function of nicotinic receptors. Whether modulation of nicotinic receptors would alter the effects of nicotine on the brain, I don't know; some people have indicated that tobacco induces strong responses during DXM use. Sigma agonists (and/or possibly antagonists) seem to affect memory function, reversing the impairment in memory caused by drugs such as p-chloroamphetamine and MK-801 (a drug similar to ketamine) (131,132). DTG, (+)-pentazocine, and SKF-10047 all improved memory impairment due to MK-801. On the other hand, NE-100, which is considered a sigma antagonist, seems to help with NMDA antagonist induced memory impairment as well (107-108). DTG, a sigma agonist, reversed the memory impairment caused by carbon monoxide (118). Many drugs now considered sigma antagonists or agonists may in fact be partial agonists. Another possibility is that the optimal level of sigma activity may be a healthy medium; one study found a bell-curve dose response on sigma agonists (118). This is similar to the effect of many nootropics (smart drugs), specifically the cholinergics - taking too much can be worse than taking none at all. This similarity may be further evidence for the link between sigma receptors and acetylcholine receptors. Both sigma1 agonists and antagonists may protect NMDA receptors from glutamate toxicity (109). One study found that sigma antagonists protected hippocampal cells from hypoxia and hypoglycemia (105), and this may be related to NMDA receptors as well. Morphine has indirect effect on NMDA receptors that seems to be mediated via sigma receptors, probably sigma1 (110). It is possible that all these effects are mediated via the nicotinic receptor, i.e., sigma1 may not directly control NMDA functioning. Behavioral Effects The behavioral effects of sigma1 receptors have not been fully established. However, sigma1 (and sigma2) receptors seem to have effects on motor function, producing an increase in locomotion (113,114,121). Part of this effect may occur at the cerebellum (113); the release of dopamine may also be involved (114,129). This is probably the origin of DXM's curious effects on motions and gait, including "sea legs" and the "Robo Shuffle". Sigma1 activation may counteract some of the analgesic effects of opioids (119). Pentazocine (Talwin), a synthetic opiate, is a potent sigma1 agonist which tends to be self-limiting; when too much is taken, the sigma activity reverses the opiate activity. It is possible that the gradual loss of euphoric effects experienced by morphine and heroin users may be related to changes caused by sigma activity. Sigma receptors seem to be involved in psychotomimetic (literally "psychosis-like") effects from schizophrenia and drugs (46-49). Amphetamine psychosis, a temporary condition resulting from heavy use of psychostimulants, may be due to sigma1 activity (80,126). Sigma, and in particular sigma1, receptors may be altered by schizophrenia. An alternative possibility which is being studied is that some sort of chemical - produced by the body itself, or by a virus or other foreign agent - causes prolonged activation of sigma receptors, and this is one of the causes for schizophrenia (47,49). Many neuroleptics, including some of the atypical ones, are sigma antagonists (47). In addition to DXM, other recreational drugs such as PCP, cocaine, and opiates all show activity at sigma receptors (72). Chronic amphetamine use increases the number of sigma receptors (80), while chronic antidepressant and antipsychotic treatments decrease the number of sigma receptors (47,74). Sigma receptors are involved in the limbic areas of the brain (81), and thus may be involved in emotion. They are also involved in the cough reflex, and probably involved in seizures (or at least their prevention). Location and Function in the Body Sigma1 receptors are also present throughout the body. Most tumor cells express both sigma1 and sigma2 receptors (38,106). Liver and kidney cells also contain sigma receptors (124), as do heart cells (125). As stated above, the placenta contains sigma1 receptors. Sigma receptors are also present in the immune system and endocrine glands, and may be responsible for modulating these systems. There is some evidence that sigma agonists may inhibit the immune system. The widespread presence of sigma receptors may indicate some involvement in development, cellular regulation, or other basic biological process. .................................................. ............................ Sigma 2 Receptors Much of what was stated about sigma1 receptors may apply to sigma2 receptors as well. There hasn't been much time to differentiate between the two receptor types. The neurotransmitter for sigma2 receptors may be zinc ions (78), and sigma2 receptors seem related to potassium ion channels (79). The sigma2 receptor is less affected by DXM than the sigma1 receptor (58). Some of the sigma-induced potentiation of NMDA function may be due to sigma2 receptors (117). .................................................. ............................ Sigma 3 Receptors Sigma3 receptors are a new discovery (115). They seem to be linked to the conversion of tyrosine to dopamine, and sigma3 agonists may increase the rate of dopamine synthesis. DXM's potency at the sigma3 receptor is unknown, but if it binds strongly there, then increased dopamine synthesis may be partially responsible for DXM's stimulant effects. ------------------------------------------------------------------------------ What are NMDA Receptors? NMDA and Other Glutamate Receptors Most of the better known neurotransmitter systems - dopamine, noradrenaline, serotonin (5HT), and acetylcholine in particular - have modulatory roles. They are produced by a few neurons located in specific clusters, and drugs affecting them often have specific effects (recreational or medical, or both). Receptors for these neurotransmitters tend to operate fairly slowly, taking milliseconds or longer to communicate. Rather than directly changing the potential of the neuron, they often trigger second-messenger responses. On the other hand, most of the brain's regular function operates quickly, and involves the excitatory and inhibitory amino acids (EAAs and IAAs, respectively). The receptors for amino acids are generally ion channels; when the receptor is activated, ions enter or exit the cell which change its potential. EAA and IAA receptors generally correspond to the positive and negative synaptic connections in electronic and computer neural networks. The excitatory amino acid neurotransmitters include glutamate and aspartate. GABA is the only established inhibitory amino acid neurotransmitter in the brain; the spinal column also uses glycine. Generally, glutamate is more prominent (or at least better understood) than aspartate, although they have similar effects at EAA receptors. Thus, the receptors for EAAs are called glutamate receptors. There are currently four identified type of glutamate receptors. Two of them, the AMPA (formerly quisqualate) and kainate receptors, are ion channel receptors which increase neuron activity in response to EAAs. A third, the metabotropic glutamate receptor, is a newer discovery, and seems to involve second messenger systems and produce metabolic effects. The fourth is the NMDA receptor. .................................................. ............................ NMDA Receptor Function and Structure o-----------------------------------------------------------o | Mg++ Zn++ | | ____ __ Asterisks (*) | | | \* _*| | indicate location | | | |_ | | of binding sites | | EAA --> * > => _> | | on the NMDA channel | | | | _| _| | | | | <_ <= \* <-- Gly | | | | | | | | OOOOOOOOOOO | | | | OOOOOOOOOOO | | ||||||||||| | / | | ||||||||||| | | ||||||||||| | <* | | ||||||||||| <-- Cell Wall | | OOOOOOOOOOO | PCP\ | | OOOOOOOOOOO | | | | | | | | | | | | | | | _ | | | <-- NMDA Channel Complex | | \/*\/ *\___/ | | | | Polyamine Mg++ | | | | Figure 8: NMDA Channel | o-----------------------------------------------------------o This drawing represents the structure of the NMDA receptor, according to current knowledge. The NMDA receptor has seven distinct binding sites. Three of these are located on the exterior surface of the cell, two are located on the cell interior, one on the inside of the channel, and one (the magnesium ion site) is present both on the inside and outside surfaces. There are two agonist sites on the exterior are the cell, denoted EAA and Gly; they correspond to the excitatory amino acids (glutamate and aspartate) and glycine. Both sites must be occupied before the channel can open enough for any ions to pass through. A third site is the target of zinc ions (Zn2+), which block the channel when present. The exterior of the channel contains a magnesium ion site. This site is also present on the inside of the cell (alternatively, it may be located within the channel itself). A magnesium ion normally occupies the exterior site; the interior site is probably empty under biological conditions. The interior of the cell contains two binding sites. One binds to polyamines (spermine and spermidine), and its function is unknown. The other, not shown in this diagram, is a phosphorylation site. Enzymes can bind to this site and enhance or reduce the activity of the receptor. o---------------------------------o o---------------------------------o | /:\ | | /::\ | | ____ : __ | | ____ :: __ | | | Mg : __| | | | | | :: __| | | | | | : | | | | | | ::| | | | EAA | : | | | | EAA | ::| | | | | | : | | | | | | ::| | | | | | : | Gly | | | | ::| Gly | | | | : | | | | | | ::| | | | OOOOO | | : | | OOOOO | | OOOOO | | ::| | OOOOO | | ||||| | / : | | ||||| | | ||||| | / ::| | ||||| | | ||||| | < : | | ||||| | | ||||| | < ::| | ||||| | | OOOOO | \ : | | OOOOO | | OOOOO | \ ::| | OOOOO | | | | : | | | | | | ::| | | | | | : | | | | | | ::| | | | | _ | : | | | | | _ | ::| | | | \/ \/ : \___/ | | \/ \/ :: \___/ | | : | | :: | | \:/ | | \::/ | | Na+, K+ ions | | Na+, K+, Ca++ ions | | | | | | Figure 9: Partially Open | | Figure 10: Fully Open | | NMDA Channel | | NMDA Channel | o---------------------------------o o---------------------------------o Finally, inside the channel itself is the PCP1 site, where PCP, ketamine, MK-801 (dizocilpine), DXM, and dextrorphan all bind. The channel must be fully open for these drugs to enter; once in place they "clog up" the channel. NMDA receptors are unique for several reasons. Unlike most receptors, they require two agonists (glutamate or aspartate, plus glycine) before the channel opens. These two agonists (Glu and Gly in the diagram) bind to two different locations on the NMDA receptor. After both agonists have bound to the channel, it opens enough for potassium to enter, and the receptor operates much like AMPA and kainate receptors. This is shown in Figure 9. The most important and unique characteristic of NMDA receptors, though, is what happens next (Figure 10). Normally, a magnesium ion is bound to a specific location at the opening of the channel; this ion allows potassium to pass through but prevents calcium, possibly due to its size. This binding is due to electrostatic forces; the same electrostatic attraction that causes potassium ions to enter the cell makes the magnesium ion cling to the channel. Once the cell becomes activated enough, however, the cell potential rises enough that the magnesium ion is no longer stuck to the cell. Calcium can enter (and exit, although this doesn't happen) the cell through the fully open NMDA channel. Once inside, calcium sets into motion a series of responses which enhance the strength of the synapse. So what's the point? Well, if the neuron is only slightly active, the NMDA channel may open partially, but the magnesium ion won't get a chance to leave its binding site. However, if the neuron should be rapidly or substantially activated, the magnesium ion will be released, and calcium can enter the cell, enhancing synaptic strength. This process, called Long-Term Potentiation (LTP), is one of the mechanisms by which neurons can change their functioning and "learn". LTP in the hippocampus is probably responsible for short-term memory. Learning capacity may in fact be directly related to the number of NMDA receptors in the hippocampus (where short-term memory is thought to be stored) (88). LTP is reversible, and long-term memory seems to be stored via more permanent changes in genetic expression and synaptic shape. There are at least three types of NMDA receptors (in the rat, at least; this probably extends to humans as well). One type is found in the cerebellum, one in the thalamus, and one in the cortex. These types differ subtly, but it is possible that DXM may show a different spectrum of effect on these types than other NMDA antagonists (such as ketamine or PCP) (87). There is also some speculation that the NMDA receptor's ion channel may (for reasons unknown) become "uncoupled" from the receptor itself (63). Noncompetitive antagonism of NMDA receptors by the open channel blockers is known to induce changes throughout the brain. NMDA blockade causes an increase in dopamine release in the midbrain and prefrontal cortex (63). NMDA blockade also causes activation of 5HT systems specifically targeting the 5HT1A receptor (90). .................................................. ............................ NMDA and Excitotoxicity NMDA receptors are involved in excitotoxicity (nerve cell death via over-stimulation). The chemicals which agonize (activate) NMDA receptors can also kill the very same nerve cells they are activating (19). Many substances, such as quinolinic acid (a metabolite of tryptophan) are so potent that very small amounts can devastate great numbers nerve cells. Others, like glutamic and aspartic acid, are less potent but still capable of doing damage if present in sufficient amounts. This excitotoxicity is directly responsible for much of the damage attributed to various types of trauma and insult to the CNS. Polio is a good example; by blocking the activity of quinolinic acid, all the damage resulting from poliomyelitis can be prevented (30-31). DXM is not a particularly effective NMDA open channel blocker, but DXO, PCP, ketamine, and MK-801 (dizocilpine) are all very effective blockers. Unfortunately, nothing in life is ever free. Lowered NMDA activity, called NMDA Receptor Hypofunction (NRH), seems to be itself responsible for excitotoxicity to other neurons. The theory is that normal NMDA activity keeps other neurotransmitters (glutamate and acetylcholine, and possibly dopamine) from being over-secreted. NRH releases this inhibition, and can therefore lead to hyperactivity at some neurons. It is possible that chronic NRH may be a cause for, or at least a factor in, schizophrenia and Alzheimer's disease (101). Acute, strong NRH of the type produced by the dissociative anesthetics has not been studied. My hunch is that it probably isn't nearly as traumatic to the brain as long-term NRH; otherwise, John Lilly would be a lot dumber than he is. DXM in particular may be safer due to counteracting effects of sigma activity. On the other hand, PCP has been shown to be toxic to neurons in the posterior cingulate, retrosplenial cortex, and cerebellum (136). This is probably a result of NRH, although sigma receptors may be involved. Infants may be particularly susceptible to this effect, so use of any NMDA antagonist during pregnancy or nursing is probably a bad idea (113). ------------------------------------------------------------------------------ What are PCP2 Receptors? PCP2 receptors were, obviously, the second PCP receptor to be positively identified (the first is the open channel site on the NMDA receptor). Their use by the body (if they have one) has not been determined. Most research indicates that the PCP2 receptor is the dopamine reuptake complex, the very same one targeted by cocaine and the antidepressant bupropion (Wellbutrin[tm]) (70,127). A reuptake complex (or reuptake site), incidentally, is a structure on a cell which takes used neurotransmitter back into the cell for recycling or breakdown. By blocking reuptake of a neurotransmitter, its activity can be increased. The tricyclic antidepressants block the reuptake of noradrenaline, dopamine, and/or serotonin (5HT). Fluoxetine (Prozac[tm]) is a serotonin-specific reuptake inhibitor (SSRI), as are several other newer antidepressants. The dopamine reuptake site seems to be the only reuptake site targeted by recreational drugs (primarily cocaine). Curiously, bupropion, a dopamine reuptake inhibitor, seems to have little recreational use potential; then again, it isn't a particularly strong dopamine reuptake inhibitor. ------------------------------------------------------------------------------ What are Na+ and Ca2+ channels? Sodium and calcium ion channels are two types of voltage dependent ion channels. These channels open or close not due to neurotransmitters, but instead due to voltage differences between the inside and outside of the cell. Voltage dependent sodium channels are typically involved in the action potential - a domino-effect propagation of nerve impulses along the axon. The sodium channel opens when the voltage reaches a certain activation threshold; the resulting influx of sodium then further activates the neuron (leading to more sodium channels opening). Eventually a second part of the sodium channel closes (otherwise they would keep themselves open forever). Incidentally, voltage dependent potassium channels are involved in bringing the neuron back to its resting state. Voltage dependent calcium channels are similar to voltage dependent sodium channels, and typically open on activation voltages. Their effect, however, is to cause calcium to enter the cell; the calcium then acts as a messenger to intracellular mechanisms. The most common example is at the end of the axon, where calcium influx causes neurotransmitters to be released. NMDA receptors may be structurally related to voltage dependent calcium channels. DXM has recently been found to block sodium and calcium channels, although it is not particularly potent in this capacity. Because of their extensive presence, blockade of these ion channels could have overall depressant effect upon brain function, and might explain DXM's toxic effects at very high dosages. ------------------------------------------------------------------------------ How does DXM compare to other drugs at these receptors? PCP and ketamine both bind more strongly to NMDA, and less strongly to the PCP2 and sigma sites, than DXM. In fact, some users report that DXM, at higher dosages, begins to resemble ketamine and PCP. The resemblance is still fairly limited. DXM's unique characteristics are most likely due to the PCP2 and sigma sites. ------------------------------------------------------------------------------ Endopsychosin and the Big Picture For whatever reason, some people involved in biological sciences like to talk about the "big picture." I'm one of them. I think the reason why the "big picture" seems so important is that science, especially biological science, has become so specialized and compartmentalized that it's difficult to keep one's perspective, especially when considering the possible relevance of things. Endopsychosin (en-doe-sy-KOE-sin) is the name given to an endogenous ligand for the NMDA open channel site (PCP1) and/or sigma receptors. The search for endopsychosins started several years ago in an attempt to find the endogenous ligand for PCP; at the time, the term was "angeldustin". Recently, the search for endopsychosins has resumed as NMDA and sigma receptors have become increasingly understood. As I write this, nobody has managed to positively identify an endopsychosin, although there are several candidates. The most promising candidates for the NMDA PCP1 site seem to be series of peptides (99-100). The endogenous ligand for the sigma1 site may be an unknown aromatic chemical (98,100). The original idea behind endopsychosin (or angeldustin, if you prefer) was that the body was capable of secreting a substance which would mimic the effects of PCP on the brain. It may be secreted in times of extreme stress, leading to a sort of detached, dreamy feeling. Endopsychosin may be responsible for such altered states of consciousness as religious ecstasy, speaking in tongues, possession, astral projection, and other paranormal experiences. Spontaneous releases of endopsychosin may account for experiences such as alien abductions, encounters with ghosts, and that sort of thing. Note the similarity of these experiences with aspects of DXM, ketamine, and PCP drug trips. In particular, the "emergence phenomenon" identified with ketamine (and present also with PCP and DXM) often consists of experiences with spiritual or alien beings. What's going on here? Why the hell would the human brain secrete a chemical that makes us think we've been talking to Elvis and Jim Morrison on the far side of Mars? What's the big picture? Well, to be honest, nobody knows. One potential clue is that the perforant path of the hippocampus (a neural circuit) seems to release endopsychosin when stimulated (141). Perhaps endopsychosin is a part of the memory process; or perhaps it is involved in dreaming and the conversion of short-term to long-term memories. Another possibility is that endopsychosin is one of the brain's natural defenses against injury. I find it interesting that sigma/NMDA agents often mimic fever hallucinations; common characteristics include Lilliputian hallucinations (feeling too big and/or too small), geometrical and linear hallucinations, and psychosis-like effects. Perhaps the brain secretes endopsychosins during high fever in an attempt to prevent neurotoxicity. In addition to potential neuroprotective roles, these substances may have significant roles in regulating cognition and (in the body) the immune and endocrine systems. A dysfunction of an endopsychosin, or of the sigma receptors (or both) may be one of the causes of schizophrenia. And if some steroids (e.g., progesterone and testosterone) turn out to be endopsychosins, this could explain a lot about the long-term behavioral effects of steroid use. Or, it may simply be that altered states of consciousness are a natural part of animal life, and that our culture's fear of such states is abnormal. Certainly one doesn't need drugs to achieve altered states; even profoundly dissociative states can be achieved with a certain amount of ritual and faith. Most "primitive" cultures have some experience with dissociative states such as astral projection, shamanic journeying, possession, and that sort of thing. They may very well know something that we don't. So it is entirely possible that the similarity between NMDA PCP1 and sigma receptors has a purpose. In any case, data about the effects of sigma-specific agonists (or antagonists for that matter) are limited, but our understanding of these receptors should improve in the next few years as research continues. Not to mention the possibility of some brave and/or stupid psychonaut deciding to experiment with sigma-specific agonists. (+)-3-PPP and SKF-10,047 are good sigma-specific ligands; more sigma1 specific ligands include 1-phenylcycloalkanecarboxylic acid derivatives (123,128). =========================================== DXM OTHER USES: One area in which DXM (as well as other NMDA blockers; see 5.3 - NMDA Receptors) shows great promise is in the prevention of brain damage resulting from excitotoxicity (over-stimulation of nerve cells to the point of cell death) and other types of nerve cell damage (19). DXM may reduce or eliminate the brain damage resulting from conditions such as fever, hypoxia (lack of oxygen) (20), ischemia (cutoff of blood to brain cells) (21-22), physical injury (23), infection (such as poliomyelitis, encephalitis, and meningitis), stroke, seizure, drug toxicity (24-25), and withdrawal from long-term dependence upon certain drugs (notably alcohol, barbiturates, and benzodiazepines such as Valium[tm]) (26-29). I apologize if this post is difficult to read. Please complain to me here or via PM if you would like me to reword or re-emphasize certain areas. I found the DXM User's Guide to be quite informative on the effects of DXM, thus I blatantly copied much of it in the 2nd half of this report. HOWEVER, the first half was 'discovered' by me--and I left it in the original order of similarities that I found... so, it shows the order in which I quite accidentally 'uncovered' many similarities between Ibogaine and DXM... I hope this will incite others to explore the usefulness of DXM--not just as a 'possible' drug for opiate WD's, but hopefully as a piggy-back, riding on the successes of the highly-touted African Iboga. -RS
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#3
12-04-2006, 01:49
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Really awesome post. Before I came here I was an avid member of one of the very large DXM sites. Have you posted this anywhere else? I know a lot of people who'd be interested in reading it.
In particular, though, the site I am talking about requires users to write an essay before they are allowed to use their forums :/ haha, so you might not be interested.
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#4
12-04-2006, 01:57
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Here is my working list of proposed drugs that have been shown to assist in treatment of, cure or help ease opiate addiction, or to decrease opiate withdrawal symptoms in the addict. I have divided up various drugs by assorted known mechanisms of action and/or known helpful primary or side effects. ------NMDA ANTAGONISTS---- Ibogaine--from the African plant Iboga. Given in a Single Administration Modality. Lotsof Procedure of Ibogaine Addiction Interruption: Quote:
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1. Taking a 3rd or 4th plateau dose while reflecting constantly on the change you wish to make in your life... and how that opiates are NOT your friend. 2. Taking a small dose (30-60mg?) each day as you taper down and after you quit your opiate of choice. 3. Taking a small dose before one 'trip' dose where you will essentially purge yourself of the opiate desire, possibly followed by small doses in the following days...? 4. ??Something totally different altogether?? ----Opiate Receptor Agonists, Partial Agonists, Antagonists, etc.---- Kratom: naturally-growing herb from Tailand. Currently legal in the U.S. Active constituent: mitragynine, 7-hydroxymitragynine, other indoles. Dose Range: 5-15 grams dried leaf (orally). Appears to be an opiate receptor agonist, but AFAIK, it is NOT an opiate and will NOT turn up positive on a drug screen. Quote:
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I recommend taking bupreprenorphine at a MUCH smaller dose than is FDA-approved and being used in the US for opiate-addiction. I remember the days when you could only get this drug from foreign countries (mexico, tailand,etc.) and I think it came in 0.2mg tablets. The way to come off opiates without any significant withdrawal symptoms was to wake up about 2 hours earlier than usual and place 2 tabs under your tongue (.4mg) and fall back asleep. Then, when you woke up to face the day, you felt great. Redose in the early afternoon. This first day was followed by about 3-4 days of the same dosage. Then, you can start shaving off the dosage of bupe. In fact, people would split pills in half... then half of halves, then half of THOSE pieces, and so on. It really doesn't take much drug at ALL to work. Then, once you run out of bupe, you're good to go. Opiate-free. Totally painless. BTW, good rule of thumb is 1 week of Bupe for each year of addiction. One good thing about Bupe, is that it is a partial antagonist just as much as it is a partial agonist. This means that if you are taking MICROSCOPIC amounts of it every morning, then you are basically blocking out your opiate receptors for another good 24-48 hours. This means that you will NOT get off if you slip-up and a 'buddy' gives you some of your former drug of choice. This is useful for flattening out your positive reinforcement conditioning that is so vital for addictions to persist. ------PHYSICAL SYMPTOMATIC RELIEF FROM WITHDRAWAL---- Loperamide (Immodium)--this will basically allow you to kick the opiates without having those miserable stomach cramps, the diarrhea, all the discomfort around the GI tract. As is already said in the sticky on how to kick the habit, take as much as you need. Clonidine: an alpha-1 adrenergic blocker. This is recommended by many addiction-specialists for those kicking opiates. It will cut back on the shakes, the shivers, the chills, the sweats, and some of the 'wired' discomfort associated with withdrawal. There are others in this category. Tenex: also an alpha-1 blocker. Propanolol (inderall), Atenolol, Metoprolol, & many others. Beta- adrenergic blockers. These slow the heart and decrease blood-pressure. also provide a calming, anti-anxiety effect. **Labetalol: Combination beta-blocker and alpha-blocker! In theory, this should be superior for its combined effects: calming alpha-mediated symptoms of WD and providing 'calming,' anti-anxiety effect of a beta-blocker. ------PSYCHOLOGICAL RELIEF FROM WITHDRAWAL (MOOD LIFTERS)---- ---this portion is incomplete. It will explore various anti-depressants, including those that have been used throughout history... SSRI's: Serotonin reuptake inhibitors. Prozac, celexa, lexapro, paxil, and others. These drugs take 2-6 weeks to work. WELBUTRIN: Increases Dopamine. Takes up to 2 weeks for full effects, although some effects can be seen immediately. NERI: NorEpinephrine-Reuptake Inhibitors; including Strattera--the new treatment for ADHD. Strattera takes almost 3 weeks for full effects, but increased energy and decreased need for stimulant meds can be seen as early as the 2nd day. Provigil: modafanil (adrafanil is the older, shorter-lived version). expensive. Promotes wakefulness. Great for staying awake during the day (after WD?). ------SLEEPING IT OFF ??---- EXPLANATION: I've considered the possibility of stocking up on benadryl and maybe some other sleeping pills and possibly benzos like valium or xanax and just SLEEPING for 3-4 days! (more on sleeping several days at the very end of this post!!) Of course, you will not want to take MORE than the recommended number of sleeping pills at any one time... you would just take sleeping pills and sleep. Then, when you wake up 6-10 hours later, take more sleeping pills and sleep... etc. etc. Sounds good in theory, but you will need several days off from school or work. You will certainly be squeaky when you emerge from this self-induced Rumplestiltskin state. Diphenhydramine (benadryl): These induce sleep. The pills come in 25mg size, but if you become tolerant to them, I've heard that you easily can take up to 75mg without fear, making you tired and causing you to sleep like a baby. Doxylamine Succinate (nyquil): From an older post by SandsofTime: Quote:
Benzo's, ambien, sonata, lunesta, etc. ok I guess, but these are also illegal without a prescription... and could be dangerous especially if you just end up replacing one addiction with another. Others: Other Sleep-Inducing Medications, primary effects usually anti-depressant, anti-psychotics, mood-stabilizers. Traza |
